Side chain halogenation of alkyl thiophenes



Patented Feb. 12, 1952 UNITED STATES PATENT GFV'FYIICELI' SIDE CHAINHALOGENATION' OF' ALKYL THIOPHEN ES John T. Clarka; Columbus, ()hig;assignor to The Texas Company, New York, N...Y. 8, C 0 l lp 0l 3 1 tionof Delaware No Drawing. Application N0vember 14,-1947,

.SerialNo. 786339:

1 This invention relates to qthe halogenationof alkyl derivatives ofthiophene More particu: larly, it relates to a method of halogenatingalkyi thiophene compounds so that predominantly side chain halogenationis effected. i

Halogenation of alkyl thiophene compoundsbv 1 heretofore knownprocedures has preferentially, resulted almost exclusively innuclearhalogenated thiophene derivatives. Prior art methods ofhalogenating thiophene are summarized in Steinkopf Die Chemie desThiophenesj wherein it is stated on page 45 that thiophene homologs areonly halogenated in the side chain after the nucleus is'fullyhalogenated as contrasted with the homo-- logs of benzene in whichnuclearhalogenation is obtained in the cold with a catalyst andsidechain halogenation takes place in sunlight with heating-. Steinkopffurther states that sidechain' halogenated de ivatives of thiophene areprepared by reactin V thiophene homologs; containinghydroxyl-substituted alkyl groupswith hydrogen chloride or hydrogenbromide. experiences of previous investigators, I have dis- Contrary ;tothe I covered that alkyl thiophene compounds can be halogenated to formmono-halederivatives-in,

which the side chain isomer predominates. Em-

p ay e et od d iti -r ci ed: n;

this reaction, it is possible-to-chlorinate a thiophene homolog andobtain -a,inono-halogenated fraction comprising more than -70 per;centside chain substituted isomer.

In a co-pending application, Serial No. 692,387,

of Lawrence, De nene ed; u r;Ha e i t fa. h Q ben i t: -2 fl f now; U.S. Patent No. 2,533,09.8,- issued;Dec; 5, 1950 there is described acontinuous ;method; of f ec n ,nuc r,. l sen 2 f. hbnhwemm pounds whichcontain; at least one reactive nu;

earh dmee at m-1 AS t rast dw th heno:

pending application the present invention con ern d w m whe y. cle n abe a on..-

of alkyl thiop e e; omol s is; m n miz d; n 61 11 15 .ha pse a n of t ih nehomolossa rremeted;

na corda c h t v tion; ha o en tion,

0i alk i er v s :v tt iq he e icont q edc 9 in he r d to rises pr d mi ai v v sid hata alosen t mppun s h r: h n nu:- clear ha o enat d eri v sb eac a-ana kyh h ophe ec mpo nd w t ha o en;atanfl i' ted; temperaturer out 1 5.0, and;. rel rablv;- n;

on ucted inthe resencebsen ep a i entuq tastar o etrach r de; I

.The proces 0f hennventio is espec a ly;

FyDPedt the .production of side chain monohalogenated thiophenederivatives. It is possible t0 DlQdilQQ Predominantly mono-halogenated"thiophene derivatives by mixing thiophene homo logsandhalogeninathorough and efiicient mannervat reaction temperature.Means for efiecting such rapid and thorough mixing whereby mono? halogenderivatives predominatein thefproducti will berdescribedhereaften IngeneraLjany of thewell known means for efi ecting instantaneous Aand;thoroughmixing o f-gaseous reactants may bepmployed.

taining otherradicals such as. a nitro group or a ,hydroxy; group onthethiophene nucleus may] alsobe used asthe organic reactant. The organicreactant may also .bealkyl thiophenederivatives in which the alkylgroups contain substituents such as a hydroxyl group, a sulphonic'. acid'group,'

, or a nitro group. In general, anyfalkyl deriv'a;

tive -of thiophene containing, a reactive replaceable hydrogenatom inthe alkyl side chain may.

er mnlqve Both chlorineand bromine can be used inthe .proce ssghowever.chlorine is more reactive sothat chlorinationallows the use of higherthroughput rates than bromination while still producing equivalentquantities of theside chain halo derivatives. Ingeneral the use ofbromine as the halogen; reactant will, necessitate; slower feed ratesand a higher mol ratio of alkylthiophen'e to, halogen than thecorresponding chlorination reaction. Equimolecular mixtures of chlorineand bromine may also be employed to produce mainly" bromine, sidechainsubstituted Droduct..

The process may be conducted in any suitable reactorwhich can withstandthe corrosive action of chlorine or bromine. and their respectivehydrohalides at elevated temperatures above 500? F.

a light source is not required to effect sidechain halogenation ofthiophene homologs, no limitai tion' is placedupon the type of reactorthat may.

be employed.

In order to-direct the halogenaticn oofv alkyl'f thiophene derivativestowards the productionoi' Thus; the-reactor may be fabricated either ofj glassor a noncorrosive metal such as stainless steel. The shape of thereactor is notimportant but as amatterv of convenience and efiiciencyofreaction, a cylindrical reactor is desirable. Since case of chlorine,optimum yields of side chain chlorinated product as measured by theratio of side chain chlorinated isomer to nuclear chlorinated isomer areobtained between 600 F. and 700 F.

In the chlorination of a mono-alkyl derivative such as methyl thiopheneand tertiary butyl thiophene, it has been found that the mol ratio ofhydrocarbon to chlorine should be maintained between 1.0 and 5.0 withoptimum results being obtained at a mol ratio of about 2.0 to 3.0.Higher mol ratios may, of course, be employed but these would merelynecessitate the fractionation of large quantities of product containingunreacted alkyl thiophene in order to recover the desired side chainchlorinated derivatives. With bromine, higher mol ratios, e. g., of theorder of 3 to 5, are advantageously employed.

Side chain halogenation of alkyl thiophene compounds is generallyeffected at atmospheric pressure. However, pressures ranging fromatmospheric to about 250 pounds per square inch and more may beemployed. As a general proposition, variation in pressure seems to havelittle directive influence on the course of high temperaturehalogenation of alkyl thiophene compounds.

Side chain halogenation of alkyl thiophene compounds is effected at aspacevelocity of at least 50 volumes of liquid alkyl thiophenederivative'per hour per volume of reactor space. Hereafter, wheneverspace velocities are used, the values will be based on a volume ofliquid thiophene derivative per hour per volume of reactor space. Spacevelocities of between about 50 and 200 can be employed in thehalogenation but space velocities of 60 to 150 are preferred. Whenchlorine is used, space velocities between about 70 and l20 aregenerally employed. As a general proposition, space velocities should bemaintained above a minimum of about 50 in order to prevent burning ofthe reaction mixture.

As heretofore mentioned, the side chain halogenation of alkyl thiophenederivatives can be effected in the presence or absence of diluents.Carbon tetrachloride is the most widely used diluent but other compoundssuch as hexachloroethane which are inert under reaction conditions mayalso be used. The halogen charge may also be diluted with inert gasessuch as nitrogen.

In carrying out the reaction in accordance with the method of thisinvention, the alkyl thiophene derivative is preheated to approximatelyreaction temperature, i. e., about 450 F. to 750 F. prior to mixing withhalogen. It is necessary to preheat the alkyl thiophene compound toreaction temperature prior to mixing because otherwise nuclearhalogenation would take place during the period wherein the mixture ofhydrocarbon and halogen is raised to reaction temperature. It isadvisable to effect rapid and thorough mixing of the alkyl thiophenewith the halogen in order to obtain high yields, of monohalogenatedproduct and reduce the yield'of poly-halogenated derivatives.Apparently, if in efficient mixing is effected, there occurspolyhalogenation of the alkyl thiophene molecules which are surroundedby a. dense concentration of halogen.

There are many methods of effecting rapid and thorough mixing of thereactants; one of these methods which has been found most effective isto employ an aspirating principle wherein the halogen is introducedthrough a small orifice into the alkyl thiophene stream at a point Wherethe alkyl thiophene is passed through a constriction in the conduitleading to the reaction vessel; rapid and efficient mixing is effectedin the constriction as a result of the turbulence caused by the highvelocity of the thiophene compound passing therethrough. Otherwell-known means of rapid and efiicient mixing of gases such as anannular atomizer type mixer may also be employed.

The halogenated compounds produced by the reaction may be recovered fromreaction products in accordance with conventional methods of recovery.For example, the reaction products of a typical chlorination containingunreacted alkyl thiophene, hydrogen, hydrogen chloride, cracked products'of charge stock, and chlorinated alkyl thiophene derivatives may becooled so as to condense normally liquid products. The condensed liquidproducts can then be treated with solid sodium bicarbonate to neutralizeany dissolved hydrochloric acid and then fractionated at reducedpressure into fractions comprising the different chloro isomers. Eachfraction is thereafter subjected to a series of tests whereby it ischaracterized as a nuclear substituted or side chain substitutedderivative and as a monoor poly-halogenated compound.

In order that the invention may be ore fully understood, reference isnow made to e following specific examples to illustrate the preferredembodiment of the invention; in all the subsequent examples thereactants were mixed by means of an aspirator mixer as described in theprevious paragraph.

In the subsequent examples, tertiary butyl thiophene and methylthiophene are chlorinated over a temperature range from about 400 to 700F. The means whereby the side chain and nuclear substitute mono-isomerswere differentiated from one another are summarized as follows:

The nuclear and side chain chlorinated derivatives of methyl thiophenewere differentiated by means of aqueous silver nitrate; chlorineattached to the nucleus is stable to aqueous silver nitrate, whilechlorine, which is substituted in the side chain is removedquantitatively by means of aqueous silver nitrate. Further, the nuclearchlorinated derivative of methyl thiophene had a boiling point of 126 F.at 20 millimeters, while the side chain-chlorinated derivative had aboiling point of 167 F. at 20 millimeters; the literature values of theboiling point of these compounds are respectively 309 F. at 738millimeters for the nuclear derivative and 347 F. at 760 millimeters forthe side chain derivative. These two properties, namely, reactivity toaqueous silver nitrate and boiling point were sufiicient todifferentiate the nuclear and side chain mono-chloro isomers of methylthiophene.

Literature values were not available for the nuclear and side chainchlorinated derivatives of tertiary butyl thiophene so that it wasnecessary to prepare these compounds in pure form by various methods.The nuclearderivative, namely 5..-

chloro-2-tertiary butyl thiophene, was preparedv by two methods: first,2-chloro-thiophene-was; alkylated with isobutylene; second, Z-tertiarybutyl thiophene was chlorinated at room temperature in accordance withthe method de-. scribed in the previously mentioned-co-pending;application, Serial No. 692,387. 5-chloro-2-tertiary butyl thiopheneprepared bythesemethods:

has a boiling point of398 F. at atmospheric pres- Z-tertiary butylthiophene was separately pl?- heated to about 400 F. Immediatelythereafter, chlorine gas was continuously introduced into the hot alkylthiophene vapor in a manner so as to effect rapid and thorough mixing ofthe reactants. The reactants in a mol ratio of about 2.7 mols oftertiary butyl thiophene per mol of chlorine were introduced, at a spacevelocity of 74 liquidvolumes of alkyl thiophene per hour per volume ofreactor space, into an unpacked glass reaction zone in which the averagetemperature was 400 F.- After about an hour on stream, 270 grams oftertiary butyl thiophene and 52 grams of chlorine had been charged tothe reactor. A yield of. 145.9 grams of mono-chloroderivative' oft-butyl thiophene was obtained which is a 59 mol per cent yield based onthe chlorine charged. The mono-chlorinated derivative consisted entirelyof 5-chloro-2-tertiary butyl thiophene, so

that the ratio of side chain mono-chlorinated product to nuclearmono-chlorinated product was 0. I f Example II Z-tertiary butylthiophenewas separatelypreheated to about 570 F. Immediately thereafterchlorine gas was continuously introduced into the hot alkyl thiophenevapor in a manner so a's to effect rapid and thorough mixing of thereactants. The reactants in a mol ratio of about 2.27 mols of tertiarybutyl thiophene per molof I chlorine were introduced into an unpackedglass reactionzone at a space velocity of 81.3 liquid volumes of alkylthiophene per hour per-volume 6 of reactor space. After about one houron stream. about 309 grams of tertiary butyl thiophene and 69 grams ofchlorine had been charged to the reactor. 196.8 grams ofmono-chlorinated tertiary butyl thiophene was obtained which is a 60 molper cent yield based on the chlorine charged. The mono-chlorinatedderivative comprised 170.5 grams of 5-ch1orc-2-tertiary butyl thiopheneand 26.3 grams of chloro-tertiary butyl thiophene so that the ratio ofside chain mono-chlorinated 65 product to nuclear mono-chlorinatedproduct was 0.16.

Example III 2-tert1ary butyl thiophene was separately preheated to about645 F. Immediately thereafter chlorine gas was continuously introducedinto the hot alkyl thiophene vapor in a manner so as to effect rapid andthorough mixing of the reactants. The reactants in a mol ratio of about'45: to about 466 F.; immediately thereafter chlorinegasywas-continuously introduced into the chlorine =.-were,.=intmducedinto an unpacked-,- glasa. reaction. zone in whichethe averagetemperature.. was. about 645 F. ata space velocity of-77.3 1iquld;;volumesof alkyl thiophene per hour per volume of reactor, space. Afterabout 25 .minutespn stream, 114 grams of tertiary butyl thiophene and 28grams, of chlorinehad been cha ged; tothe reactor. A;yi e1d-of 73.2;grams of mono-chlorin ated. tertiary -butyl thiophene was obtained,

which is a; 55 molper centyield based on the, chlorine charged.Themono-chlorinated derive: tive.co ntained 18.6; grams of;5-chloro-2-.tert iary;- butyl-thiopheneand 54.6 grams ofchloro-tertiary; butylthiopheneso that theratio of-sicle chainmonoachlorinated product to nuclear mopo chlo l.

heated to; about 6552-1 immediately thereafter,

chlori gaswas continuouslyintroduced into the hot .alkyl thiophene vaporin a manner. so as to effect rapid and thorough mixing of the.

reactants, The reactants in av mol ratio of 1 about 2.2 mols of tertiarybutyl thiophene. per

mol otchlorine were introduced into an unpacked reaction zonein whichthe average temperature was about 655 F. at a space velocity; of79.8-liquid'volumes of alkyl thiophene pen, hour per volu ne of reactorspace. After-about; 55 minutes on stream, 276 grams of tertiary butylthiophene and 63 grams of chlorine had;

A yield of 189.1

been charged to the reactor. grams of mono-chlorinated tertiary butylthiophene was obtained'which is a 63 mol per cent yield based on thechlorine charged. The monochlorinated derivative consisted of 63 grams,of

5-chloro-2-tertiary butyl thiophene and H 126- grams. of chloro-tertiarybutylthiophene so that theyratio ofsidechain mono-chlorinated product;

to nuclearmono-chlorinated product was 2.0.

Epample V 4 2-methy1 thiophene was separately preheated hot .alkylthiophene vapor inra manner so as to effect rapid and thorough mixing ofthe reactants. The reactants in the mol ratio of about 80 4.5 molsofjmethylthiophene per mol of chlorine wereintroduced at; aspacevelocity ;of -119.5-1iq-. uid volumes of 1 alkyl thiophene perhour pervolume of reactor space into an unpacked glass, reaction zone in whichthe average temperature 5 wasabout 466 F. After vabout two hours on.stream, 487-grams ;of methyl thiophene and79'. grams of chlorine hadbeen charged tothe .re-e

actor. A yield of 56.8 grams of mono-chlorinated methyl thiophene wasobtained which is a 60 53.3 mol per cent yield based on the chlorinecharged. The mono-chloro-derivative consisted of 114.3 grams of5-chloro-2-methyl thiophene and 42.1 grams of chloro-methyl thiophene(thenyl chloride) so that the ratio of side chain mono-chlorinatedproduct to nuclear monochlorinated product was 0.37.

Example VI 2-methyl thiophene was separately preheated to about 610 F.Immediately thereafter chlorine gas was continuously introducedinto thehot alkyl thiophene vapor in a manner so as to effect rapid and thoroughmixing of the reactants. The reactants in a mol ratio of 4.37

2.06 mols of tertiary butyl thiophene per mol of 7 mols of methylthiophene per mol of chlorine wereintroduced at a space velocity of 119liquid volumes of alkyl thiophene per hour per volume grams ofmono-chlorinated methyl thiophene was obtained which is a 49 mol percent yield based on the chlorine charged. The monochlorinated derivativeconsisted of 36.4 grams of -chloro-2-methyl thiophene and 67.2 grams ofchloro-methyl thiophene (thenyl chloride) so that the ratio of sidechain mono-chlorinated product to nuclear mono-chlorinated product was1.85.

It will be understood of course that bromine.- tion of alkyl thiophenecompounds is effected in a manner similar to the chlorination procedurewhich has been described in the preceding examples. In general, highermolecular ratios of alkyl thiophene to halogen and lower spacevelocities are employed during bromination than are used duringchlorination of thiophene homologs.

Furthermore, allryl thiophene compounds other than methyl thiophene andtertiary butyl thiophene are halogenated in the side chain by thetechnique heretofore described. It will also be understood that nuclearor side chain substituted alkyl thiophene compounds which may bevolatilized under the conditions of reaction can be I employed as acharge stock; the only requisite is that there be a replaceable hydrogenatom in the alkyl group.

In the procedures heretofore described, monohalogenated isomers havepredominated in the reaction product; it is possible to obtain a productcomprising mainly poly-halogenated side chain substituted derivatives bydecreasing the mol ratio of alkyl thiophene to halogen and by thefurther addition with thorough mixing of an additional quantity ofhalogen.

Obviously, many modifications and variations of the invention, ashereinbefore set forth, may

be made without departing from the spirit and scope thereof and,therefore, only such limitations should be imposed as are indicated inthe appended claims.

I claim:

pounds, the method of preferentially effecting substitution of the sidechain which comprises reacting an alkyl thiophene compound with halogenat a temperature between about 450 and 750 F. and at a space velocity ofat least volumes of alkyl thiophene per hour per volume of re actorspace.

2. In the halogenation, of alkyl thiophene compounds, the method ofpreparing mainly monohalogenated side chain derivatives which comprisesreacting an alkylthiophene compound with halogen at a temperaturebetween about 500 and 750 F. at a space velocity between 50 and 200volumes of alkyl thiophene per hour per volume of reactor space and at amol ratio of alkyl thiophene to halogen of at least 2.

3. In the halogenation of alkyl thiophene compounds, the method ofpreferentially effecting substitution in the side chain which comprisesintroducing an alkyl thiophene and halogen into a reaction zone at aspace velocity between about 50 and 200 volumes of alkyl thiophene perhour per volume of the reactor space, effecting reaction between feedalkyl thiophene and halogen at a temperature between about 500 and 750F., and recovering a side chain substituted halogen derivative from thereaction product.

4. 2(1,1-dimethyl-2-chloro-ethyl) thiophene.

5. In the chlorination of alkyl thiophene compounds a method ofpreferentially effecting substitution of the side .chain which comprisesreacting an alkyl thiophene compound with chlorine at a temperaturebetween 450 and 750 F., and at a space velocity of at least 50 volumesof alkyl thiophene per hour per volume of reactor space.

6. A method according to claim 5 in which the chlorination is effectedat a space velocity of to volumes of alkyl thiophene per hour per volumeof reactor space.

JOHN T. CLARKE.

REFERENCES CITED The following references are of record in the file ofthis patent:

UNITED STATES PATENTS 40;,3Number Name Date 1,428,984 Schmidlin Sept.12, 1922 2,425,721 Blicke a Aug. 19, 1947 FOREIGN PATENTS ,NumberCountry Date 378,866 Great Britain Aug. 16, 1932 OTHER REFERENCESBeilsteins Handbuch der Organischen Chemie,

d. 4, 01. 17, 44, g 1. In the halogenation of alkyl thiophene com- 18 Vpage Spun er Baum 1933 Morton: The Chemistry of Heterocyclic Compounds,p. 42, McGraw-Hill, N. Y., 1946.

Groggins: "Unit Processes in Organic Synthesis, ed. 3, p. 199,McGraw-Hill, N. Y., 1947.

Richter: Organic Chemistry, pp. 649, 650,

' Wiley, N. Y., 1938.

1. IN THE HALOGENATION OF ALKYL THIOPHENE COMPOUNDS, THE METHOD OFPREFERENTIALLY EFFECTING SUBSTITUTION OF THE SIDE CHAIN WHICH COMPRISESREACTING AN ALKYL THIOPHENE COMPOUND WITH HALOGEN AT A TEMPERATUREBETWEEN ABOUT 450 AND 750* F. AND AT A SPACE VELOCITY OF AT LEAST 50VOLUMES OF ALKYL THIOPHENE PER HOUR PER VOLUME OF REACTOR SPACE.